The proposed project aims to develop technology for identification of human DNA variation, by using high-density oligonucleotide arrays (informally referred to as DNA chips). We will focus on developing technology for two key applications. 1. Single Nucleotide Polymorphisms (SNPs). We will: (i) Develop robust methods to identify the single nucleotide polymorphisms (SNPs); (ii) Test the methods by identifying SNPs in STSs covering approximately 1.5 Mb of genomic DNA; (iii) Construct a third-generation genetic map of the human genome with 2000 SNPs, with heterozygosity approximately 40 percent and known map locations; (iv) Develop a robust genotyping system for using this third- generation genetic map, including an oligonucleotide array and efficient laboratory protocols for multiplex amplification. 2. Common Variation in Genes. Common variants in a number of genes (such as ApoE, FactorV, CCR-5, and MTHFR) have recently been shown to be associated with disease susceptibilities. Systematic application of this powerful approach to human genetics will require: (a) population surveys to identify all common variants in the genes involved in a given physiological system; and (b) association studies to correlate the common variants with disease risk. We will focus on the first task. We will: (i) Explore efficient ways to perform a population survey to discover variation in coding sequences, either by using genomic DNA or mRNA. (ii) Apply the techniques to identify the common variants in the genes involved in two physiological systems--(a) blood coagulation and (b) lipid transport and metabolism--already known to be the site of some common variants having important relationships to disease risk.